The present invention relates generally to the modulation of cutaneous delayed hypersensitivity, and more particularly to compositions and products capable of such modulation, and their applications.
In general, the skin like the majority of the organs and tissues of the body, possesses a defensive mechanism responsive to invasive stimuli that are perceived to be harmful to normal functioning. Such mechanisms serve in most instances to localized cellular damage by isolating the situs of injury and attacking the manifestation of the invasive stimulus. The response known as delayed hypersensitivity that is exhibited by the skin is believed to be such a mechanism. As its name implies, delayed hypersensitivity represents a condition or state that the area of skin exposed to a harmful irritant will enter after a first uneventful exposure to the invasive stimulus or irritant. The manifestation of delayed hypersensitivity may include cellular swelling, heightened tactile discomfort, lesion-like eruptions and other such adverse conditions. For example, contact dermatitis occurs when the skin is exposed to a variety of harmful irritants.
Interestingly, certain harmful stimuli tend to suppress delayed hypersensitivity and in this sense, pose other dangers. For example, severe sunburn resulting from exposure to ultraviolet radiation has been found to suppress delayed hypersensitivity, as the expected rejection of the sunburned skin cells does not take place. In particular, the exposure to ultraviolet light which causes the sunburn likewise induces other changes in the skin which are believed to predispose, or lead, an individual to skin cancer. Such exposure can cause tumor graft tolerance and suppress delayed hypersensitivity (DH) [Parrish, J.A., ed. "The Effect of Ultraviolet Radiation on the Immune System", Johnson and Johnson Baby Products Company.]. Ultraviolet irradiation of mouse skin causes tolerance to the placing of relatively immunogenic skin tumor grafts. [Krinke, J. Nat. Cancer Inst. 57, pp. 211-215 (1976)]. The extent of suppression of delayed hypersensitivity (DH) by ultraviolet light has been used to quantify immunological tolerance caused by ultraviolet light, [Noonan, Springer Semin, Immunopathol., 4, pp. 293-304 (1981) and Parrish, cited above]. Irradiated mouse skin secretes low molecular weight protein that stimulates suppressor T cells in the spleen [Swartz, J. Invest. Dermatol. 83, pp. 305-307 (1984 ) and Schwartz et al., J. Invest. Dermatol., 87, pp. 289-291 (1986)]. Moreover, the cis isomer of urocanic acid is released from irradiated mouse skin, presumably a photoproduct of the trans isomer, normally present in the skin [De Fabo et al., J. Exp. Med., 157, pp. 84-98 (1983)]. Ultraviolet photoproducts of purified urocanic acid also were able to suppress DH to herpes virus in mice [Ross et al., J. Invest. Dermatol., 87, pp. 630-633 (1986)], so there may be more than one inducer or more than one cutaneous step in this process. Neither the mechanism of action, nor the source of the active substance, has been identified with certainty. Also, it is now known what normal physiological function, if any, is served by the suppressor cells. These cells, however, prevent rejection of tumor tissue, thus allowing ultraviolet carcinogenesis [Fisher et al., Science, 216, pp. 1133-1134 (1981)].
It is obvious that ultraviolet radiation suppression of delayed hypersensitivity can prevent rejection of ultraviolet radiation exposed skin, at the risk of the long-term consequence of elevated skin tumor susceptibility. It would be advantageous to eliminate this effect in order to reduce or eliminate the possible long-term consequence of skin cancer in individuals who have sustained recent sun exposure.
An opposite result and corresponding problem exist in the instance of percutaneous drug delivery systems. For example, numerous agents that are desirably administered topically for the benefits of enhanced speed of administration have been discouraged due to the adverse side effects resulting from the adverse reaction of the skin to contact with these agents. Such materials include common drugs such as the penicillins, nitroglycerine, scopolamine, Nystatin, and others, which elicit an allergic dermatitits resulting either directly from the administration of the drug or from the vehicle in which the drug is exposed. For example, the disk variety of transdermal delivery system manufactured by G. D. Seale, Inc. elicits an adverse dermatitis resulting from the contact between the silicone adhesive and the skin. Similarly, a transdermal delivery system for nitroglycerine including propylene glycol as a part of the vehicle has elicited problems of hypersensitivity to this specific ingredient.
In this context, investigation has been initiated of certain steroid compounds to determine whether these would have a favorable effect of modulating delayed hypersensitivity appropriately to favorably address the foregoing diverse situations. The inventors herein investigated certain glucocorticoid compounds such as triamcinolone acetonide, while exhibiting certain suppressive effects upon delayed hypersensitivity, also exhibited an adverse systemic effect which rendered it undesirable as a candidate for inclusion in situations where suppression of delayed hypersensitivity is desirable. Similarly, in work performed by the present inventors and embodied in parent application Ser. No. 030,764, the disclosure of which is incorporated herein by reference, the 21-oic methyl ester of triamcinolone acetonide (TA) or TAme was found to inhibit the ultraviolet-induced suppression of delayed hypersensitivity. In the present disclosure, this same group of compounds i.e. the glucocorticoid carboxylic acid esters were further investigated and have been found to truly serve as modulators of cutaneous delayed hypersensitivity, in that, they can be co-administered with otherwise reaction-provoking compounds and will suppress delayed hypersensitivity in a highly localized manner, thus obviating the danger of adverse systemic or cutaneous effects. They can additionally be utilized in the treatment of certain disease states where a highly localized effect on the cellular immune responses in the skin is desired.
SUMMARY OF THE INVENTION
In accordance with the present invention, glucocorticoid carboxylic acid esters, and more particularly glucocorticoid carboxylic alkyl esters have been determined to exhibit a modulating effect upon cutaneous delayed hypersensitivity. Thus, the present invention includes compositions for the inhibition of ultraviolet radiation suppression of delayed hypersensitivity, for the purpose of reducing the incidence of the development of skin cancer and compositions for the inhibition of the sensitization and elicitation phases in contact hypersensitivity. Likewise, similar compositions for topical administration may be prepared comprising a glucocorticoid carboxylic acid ester in combination with one or more drugs capable of topical or percutaneous administration, which drugs exhibit by themselves an arousal of cutaneous delayed hypersensitivity. Particular compositions may be prepared in ointment, gel or spray form with conventional ingredients such as carriers, pH stabilizers and the like for topical administration.
In a further embodiment of the present invention, percutaneous drug delivery systems in the form of transdermal patches and the like may be prepared wherein the active ingredient or drug to be delivered is admixed in combination with the glucocorticoid carboxylic acid esters of the present invention in an amount sufficient to suppress delayed hypersensitivity caused by one or more of the ingredients of the percutaneous delivery system. The glucocorticoid carboxylic esters of the present invention may be embodied into each of the transdermal delivery systems including the disk system, the gel system and the layer system, all of which are well known in the art.
In the instance where the glucocorticoid carboxylic acid ester of the present invention to be incorporated into creams, gels, ointments and sprays, an effective amount of same is that concentration sufficient to yield a skin dose of from 1 to 100 micrograms per cm.sup.2 per application. In the instance where transdermal delivery systems using time-controlled delivery are involved, the dosage range of the glucocorticoid carboxylic acid esters of the present invention should be approximately 100 micrograms per 24 hours of activity.
Additionally, the glucocorticoid carboxylic acid esters of the present invention can be incorporated into a gel or paste of "spansule" or other delayed-release formulation which can be administered by injection. Such formulations can be utilized to treat internal inflammatory diseases, e.g. rheumatoid arthritis, intractable bur itis, osteogenic arthritis, and certain internal inflammatory neurological disorders, such as multiple sclerosis, amyotrophic lateral sclerosis, and myathenia gravis, which could not be treated with convention steroids due to systemic side effects. Typically, the formulations will contain the active glucocorticoid carboxylic acid ester in an amount 0.005 to 1.0 percent by weight, and preferably 0.01 to 0.2 percent by weight.
The glucocorticoid carboxylic acid esters of the present invention are easily incorporated into all of the aforementioned products with conventional processing and need only pH stabilization ear neutrality in view of the steroidal structure. Products containing these glucocorticoid carboxylic acid esters achieve unexpected improvements in administration and delivery of drugs without the harmful side effects normally experienced with steroids. Also, the compounds of the present invention employed as the sole active ingredient of topical compositions can serve to effectively treat the adverse effects of excessive exposure to ultraviolet radiation by encouraging the onset of delayed hypersensitivity and thereby reducing the incidence of the development of skin cancer. Additionally, the topical compositions containing only the compounds of the present invention can be utilized in the treatment of disease states of for the inhibition of the sensitization and elicitation phases in contact hypersensitivity.
Accordingly, it is a principal object of the present invention to prepare compositions for topical application which are capable of selectively modulating cutaneous delayed hypersensitivity without exerting undesirable systemic effects.
It is a further object of the present invention to prepare compositions as aforesaid which can suppress delayed hypersensitivity to facilitate the administration of therapeutic compounds or their carriers that individually elicit undesirable percutaneous delayed hypersensitivity.
It is a further object of the present invention to provide compositions as aforesaid which may be administered to favorably inhibit the ultraviolet radiation suppression of delayed hypersensitivity to correspondingly reduce the incidence of the development of skin cancer.
It is a still further object of the present invention to prepare transdermal drug delivery systems embodying the compositions as aforesaid.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing detailed description.